Fever is common in the intensive care unit (ICU), with an estimated prevalence at admission of up to 70%, and frequently coexists with acute lung injury (All). Although fever is considered salutary in infections, which are present in more than half of ICU patients with respiratory failure, previous studies suggest that febrile-range hyperthermia (FRH)may worsen ALL The mechanisms by which fever potentiates lung injury are poorly understood. The goal of this proposal is to examine the mechanisms by which FRH augments ALI and to determine if treatment is needed for this common ICU scenario. Our laboratory previously showed that Fas-mediated apoptosis in the lung epithelium plays an important role in the development of ALI. Other mediators of apoptosis, known as "death receptor" ligands, have also been implicated in type II epithelial cell injury and the pathogenesis of ALI. In non-pulmonary organ systems, FRH enhances apoptotic cell death caused by death receptor activation. These studies suggest that apoptosis may be an important mechanism by which FRH augments ALI. Our preliminary data show that FRH enhances TNF-a mediated caspase activity and epithelial cell death in vitro and enhances alveolar permeability in an animal model of lung injury. Our primary hypothesis is that FRH-potentiated lung injury is mediated by augmented death receptor activity on the lung epithelium. We will investigate this in three specific aims. First, using a murine model of FRH-potentiated lung injury, we will block caspase activation by death receptors using broad caspase inhibitors to determine the role of death receptor mediated caspase activation in enhanced injury. Next, we will inhibit the activity of each death receptor (Fas, TNF-a, TRAIL) to determine the relative contribution of each of the death receptor ligands to enhanced lung injury. Finally, we will explore the signaling pathway(s) by which hyperthermia augments death receptor activation in vitro. PUBLIC HEALTH RLEVEANCE: Acute lung injury is a common cause of morbidity and mortality in the critically ill. Fever occurs frequently in this population, and has been implicated to worsen lung injury. The studies in this proposal will define the mechanisms by which fever worsens lung injury and will be important in defining the best clinical approach to treatment of fever in patients with lung injury.